This invention relates to pharmacology, and to the use of dextromethorphan in conjunction with a second drug that inhibits enzymatic oxidation of dextromethorphan.
Dextromethorphan (frequently abbreviated as DM) is the common name for (+)-3-methoxy-N-methylmorphinan. It is a non-addictive opioid comprising a dextrorotatory enantiomer (mirror image) of the morphinan ring structure which forms the molecular core of most opiates. DM is widely used as an antitussive agent (i.e., as a cough suppressant) in over-the counter formulations such as cough syrup. It is also being evaluated as a possible treatment for certain types of excitotoxic brain damage caused by ischemia (low blood flow) and hypoxia (inadequate oxygen supply), which are caused by events such as stroke, cardiac arrest, and asphyxia. This anti-excitotoxic activity is discussed in items such as Choi 1987 (full citations to articles are provided below), Wong et al 1988, Steinberg et al 1988, and U.S. Pat. No. 4,806,543 (Choi 1989).
The antitussive activity of DM is believed to be due primarily to its activity at a class of neuronal receptors known as sigma receptors. These receptors are inhibitory, which means that activation of these receptors suppresses certain types of nerve signals. Sigma receptors are often referred to as sigma opiate receptors, but there is some question as to whether they are true opiate receptors, so many researchers refer to them simply as sigma receptors. Some researchers refer to "high-affinity dextromethorphan receptors;" this category apparently includes but may not be limited to sigma receptors.
The anti-excitotoxic effects of DM are believed to be primarily due to its activity at another class of receptors known as N-methyl-D-aspartate (NMDA) receptors, which are one type of excitatory amino acid (EAA) receptor. Unlike its agonist activity at sigma receptors, DM acts as an antagonist at NMDA receptors, which means that DM suppresses the transmission of nerve impulses mediated via NMDA receptors, Since NMDA receptors are excitatory receptors, the activity of DM as an NMDA antagonist also leads to the suppression of certain types of nerve signals.
Because of its activity as an NMDA antagonist which may be able to block excitotoxic damage to neurons, DM is also of interest as a potential treatment for neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease), all of which are suspected of containing an excitotoxic aspect of their etiology. Reports of this field of research include Walker and Hunt 1989, Albers et al 1991, and Applebaum et al 1991.
Dextromethorphan has also been reported to suppress neural activity mediated by neuronal calcium channels (Carpenter et al 1988).
Because DM activity apparently involves at least three classes of neuronal receptors, it is difficult to clearly attribute the effects of DM in suppressing nerve impulses to a single type of receptors. Nevertheless, the chemistry and structure of DM are well-known, and the pharmacology is described in standard texts such as Goodman and Gilman's Pharmacological Basis of Therapeutics and Rodd 1960, and in articles such as Tortella et al 1989, Leander 1989, Koyuncuoglu & Saydam 1990, Ferkany et al 1988, George et at 1988, Prince & Feeser 1988, Feeser et al 1988, Craviso and Musacchio 1983, and Musacchio et al 1988.